Highlights from Recent Cancer Literature
Journal: Cancer Research (2013)

Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 2013;19:901–8.Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME. Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem 2012;123:997–1009.Zhou W, Feng X, Ren C, Jiang X, Liu W, Huang W, et al. Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma. Mol Cancer 2013;12:53.Much effort is aimed at understanding the altered metabolic state of cancer cells and determining how altered metabolism can be targeted therapeutically. In glioma, mutations in isocitrate dehydrogenase (IDH) identify a unique molecular and prognostic subset. Tönjes and colleagues compare transcriptional profiles of tumors expressing wild-type (WT) IDH with tumors expressing mutant IDH and identify the branched chain aminotransferase 1 (BCAT1) as a strong predictor of IDH mutational status. The BCATs are enzymes important in the generation of glutamate and tricarboxylic acid cycle building blocks from the branched-chain amino acids leucine, isoleucine, and valine. Two BCAT isoenzymes exist: a cytosolic BCAT1 and a more ubiquitous mitochondrial BCAT2. Of these, BCAT1 is highly expressed in the brain and plays an important role in brain glutamate metabolism, as shown previously by Hull and colleagues. Within a large set of human tumors, IDH1-WT tumors had significantly higher BCAT1 mRNA and BCAT1 protein levels compared with IDH-mutant tumors. Furthermore, in glioma cells, exogenous α-ketoglutarate, a BCAT substrate, increased BCAT1 levels, and expression of mutant IDH1 or knockdown of WT IDH1 decreased BCAT1 levels. Although multiple factors may contribute to downregulation of BCAT1 in IDH-mutant tumors, hypermethylation appears to be a prominent mechanism, as the BCAT1 promoter is hypermethylated in IDH1-mutant tumors. Indeed, the investigators suggest that robust BCAT1 immunostaining on clinical samples can be used to identify IDH1-1 and IDH2-WT tumors. Although it is unclear if BCAT1 suppression is important for the pathogenesis of IDH-mutant glioma, Tönjes and colleagues show functional relevance for BCAT1 in IDH1-WT tumors, as knockdown of BCAT1 resulted in decreased tumor cell proliferation, decreased tumor cell migration in a microchannel migration assay, and decreased orthotopic tumor growth. Recent studies in nasopharyngeal carcinoma, including one by Zhou and colleagues, also implicate BCAT1 in tumorigenesis. Additional studies are needed to understand how BCAT1 modulates tumor metabolism and whether BCAT1 may be a therapeutic target in cancer.Dasgupta S, Menezes ME, Das SK, Emdad L, Janjic A, Bhatia S, et al. Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling. Clin Cancer Res; Published OnlineFirst July 19, 2013; doi:10.1158/1078-0432.CCR-13-0585Management of invasive urothelial cell carcinoma (UCC) is a daunting task and warrants an in-depth understanding of the molecular mechanism regulating UCC invasion and metastasis. Dasgupta and colleagues have identified a novel role of MDA-9/Syntenin (SDCBP), which is localized on human chromosome 8q12, in regulating UCC growth and metastasis. Enhanced expression of MDA-9/Syntenin was observed in primary UCC tumors and was associated with UCC progression. Expression of elevated MDA-9/Syntenin also correlated with elevated expression of EGFR, AKT, and CTNNB1, key tumor growth and metastasis regulatory molecules. Overexpression of MDA-9/Syntenin in nontumorigenic urothelial cells markedly increased their proliferating and invading capabilities and induced the epithelial–mesenchymal transition (EMT) phenotype. The phenotypic changes observed with elevated MDA-9/Syntenin expression were accompanied by upregulation of key growth-regulatory molecules, including EGFR, AKT, C-Src, and PI3K, and EMT-regulatory molecules Vimentin, TCF4, and CTNNB1. Downregulation of other key EMT-associated molecules, E-cadherin, ZO-1 (TJP1), and Claudin, was also noted in these cells. Remarkably, depletion of MDA-9/Syntenin in three UCC cell lines reversed the phenotypic and associated molecular changes observed following overexpression of MDA-9/Syntenin in the nontumorigenic urothelial cells. Moreover, depletion of MDA-9/Syntenin markedly reduced in vivo metastasis of UCC cells. Additionally, an interaction between MDA-9/Syntenin and EGFR was discovered in both UCC cell lines and primary UCC tumors. In summary, MDA-9/Syntenin appears to be a promising biomarker for UCC monitoring, and in concert with EGFR, could be an attractive target for therapeutic intervention.Zheng Y, de la Cruz CC, Sayles LC, Alleyne-Chin C, Vaka D, Knaak TD, et al. A rare population of CD24+ITGB4+Notchhi cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer Cell 2013;24:59–74.Lung cancer remains the number one cause of cancer death, underscoring the critical need for novel therapies that target this disease. Although a number of groups have described cell surface markers identifying the tumor-propagating/stem cells (TPC) driving lung tumor growth, the significance and relevance to human health of cells expressing these markers has been controversial. Zheng and colleagues identify a novel, small population of non–small cell lung cancer (NSCLC)-propagating cells marked by expression of the glycoprotein CD24, the integrin ITGB4, and the signaling receptor Notch (CD24+ITGB4+Notchhi). This population of TPC is enriched in mouse NSCLC models treated with chemotherapy, consistent with intrinsic resistance to such agents. Similar populations of cells were found in human NSCLC cell lines and primary lung cancer samples. These populations regulated self-renewal in vitro and lung tumor growth in xenograft models. The authors identified a gene expression signature from this TPC population that was prognostic for NSCLC patients. Thus, CD24+ITGB4+Notchhi-expressing cells represent a small population of cells within NSCLC that are capable of self-renewal, are relatively resistant to chemotherapy, and express a gene signature predictive of a poor patient outcome—all characteristics consistent with TPC. CD24+ITGB4+Notchhi cells also exhibited a nonredundant role for Notch3, suggesting that agents that target Notch3 signaling might exhibit a therapeutic benefit over those agents that also target Notch1 and Notch2, which displayed significant gastrointestinal toxicity in clinical trials.Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A 2013;110:11988–93.Myc is a master regulator of protein synthesis that is deregulated in several human cancers, but therapeutic approaches that directly target Myc are not yet available. The mTOR kinase is also frequently aberrant in cancer and controls protein synthesis in part through regulation of eukaryotic translation initiation factor 4EBP1 (EIF4EB1), a druggable pathway. Pourdehnad and colleagues uncover a link between Myc and mTOR-dependent 4EBP1 phosphorylation during Myc-driven tumorigenesis of human lymphomas and multiple myeloma and shed light on the therapeutic efficacy of MLN0128, an mTOR active site inhibitor that fully blocks mTOR complex1 (mTORC1) and mTOR complex2-kinase activity. The investigators used an Eμ-Myc transgenic mouse model of Burkitt lymphoma driven by constitutive overexpression of Myc, and found an increase in mTOR-dependent phosphorylation of 4EBP1 at the earliest stage of tumor initiation that was maintained during tumor progression in the absence of activation of other mTOR substrates. Treatment of these Eμ-Myc transgenic mice with MLN1028 induced apoptosis of Myc-overexpressing B cells without affecting wild-type B-cell proliferation and survival. Treatment with the allosteric mTORC1 inhibitor RAD001 failed to block 4EBP1 phosphorylation and was not effective, demonstrating the requirement of 4EBP1 in cell survival downstream of Myc signaling. In established Myc-driven tumors, the investigators found that MLN1028 similarly causes apoptosis and near-complete resolution of pathologic lymphadenopathy after only 3 days of treatment. To further elucidate this process, the investigators genetically inactivated mTOR-dependent EIF4E hyperactivation by using mouse models that specifically express an inducible, dominant-negative 4EBP1 mutant in the B-cell compartment rendered insensitive to mTOR signaling. This process dramatically reduced circulating pretumor cells due to robust induction of apoptosis, showing that 4EBP1-dependent inhibition of EIF4E activity hinders Myc-driven lymphomagenesis, and that inhibition of this pathway is a key determining factor of MLN1028 efficacy. The investigators extended these observations to multiple myeloma, a Myc-driven disease, and found analogous cross-talk between the Myc and mTOR signaling pathways at the level of 4EBP1 phosphorylation. Similarly, treatment of these cells with MLN1028 induced selective apoptosis in dysregulated plasma cells, and complete resolution of disease in vivo with restoration of normal hematopoiesis. Immunostaining of a human diffuse large B-cell lymphoma tissue microarray showed a robust correlation between high levels of Myc and 4EBP1 phosphorylation, indicating that mTOR-dependent phosphorylation of 4EBP1 is required for survival of a broad range of Myc-driven malignancies. These data reveal a previously unknown function of Myc that converges on regulation of mTOR-dependent protein synthesis, supporting pharmacologic targeting with active site inhibitors as a clinically relevant approach to Myc-driven cancers.Schade B, Lesurf R, Sanguin-Gendreau V, Bui T, Deblois G, O'Toole SA, et al. β-Catenin signaling is a critical event in ErbB2-mediated mammary tumor progression. Cancer Res 2013;73:4474–87.ERBB2 amplification is a driver in breast cancer, and drugs like trastuzumab and lapatinib are key to treating this aggressive cancer. However, our understanding of ERBB2-positive breast cancer progression and response to therapy remains limited. ErbB2 signaling has been studied in the MMTV-Neu/HER2/ErbB2 mouse model, where the oncogene is induced by hormone receptors from the mouse mammary tumor virus (MMTV) promoter sequence. ERBB2 becomes expressed at high levels in a relatively nonphysiologic manner, and growing tumors, which are always luminal in subtype, invariably carry an activating mutation. Schade and colleagues have used a newly developed mouse model (Erbb2KI) that closely resembles ERBB2 amplification in patients in which a Cre-inducible Erbb2 allele is controlled by its own promoter. The investigators found that tumor cell heterogeneity is well represented, as tumors are not only luminal but also basal in origin and, thus, show a lineage heterogeneity similar to that observed in human tumors. A distinguishing feature not obvious in the well-characterized MMTV-ErbB2 model is that ErbB2KI tumors show constitutive activation of canonical β-catenin signaling (CTNNB1), further supporting their basal origin. An important twist of this story is that β-catenin not only is a target of ErbB2 but also binds to Erbb2 regulatory sequences and drives transcription of Erbb2 itself. This finding was reproduced in human ERBB2 amplicon-positive cell lines. These data support an argument that, although ERBB2 amplification might be a key event, these cells depend on β-catenin to maintain ERBB2 expression and function. Thus, patients with ERBB2-amplified tumors with active β-catenin may be good candidates for a combination of trastuzumab or lapatinib and β-catenin/CBP inhibitors (e.g., ICG-001) that may be available in the future. Also, the inconsistent ERBB2 levels in patient-matched primary tumors, circulating tumor cells, and metastasis may be explained in part by this mechanism, whereby, despite the ERBB2 gene being part of an amplicon, changes in β-catenin transcriptional activity could affect the levels of ERBB2. Such an occurrence might also determine the effectiveness of therapies on this target, which was assumed to be constitutively present.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.